Background: Heparin has been used for years as a locking solution in totally implantable venous access devices. Normal saline (NS) might be a safe alternative for heparin. However, evidence of non-inferiority of NS versus heparin is lacking. Patients and methods: We randomly allocated 802 cancer patients with a newly inserted port either to heparin lock (300 U/3 ml) or to NS lock groups in a 1:1 assignment ratio. The primary outcome was the number of functional complications, which was defined as 'easy injection, impossible aspiration' at port access. Secondary outcomes included all functional problems and catheter-related bacteraemia. We hypothesised that NS locks do not cause more functional problems and catheter-related bacteraemia than heparin locks. Non-inferiority is established if the upper limit of the confidence interval (CI) for the relative risk of NS versus heparin is <1.4. Results: Three hundred and eighty-two patients from the NS group and 383 from the heparin lock group were included in the analysis. The incidence rate of our primary outcome (easy injection, impossible aspiration) was 3.70% (95% CI 2.91%-4.69%) and 3.92% (95% CI 3.09%-4.96%) of accesses in the NS and heparin groups, respectively. The relative risk was 0.94% (95% CI 0.67%-1.32%). Catheter-related bloodstream infection was 0.03 per 1000 catheter days in the NS group and 0.10 per 1000 catheter days in the heparin group. Conclusion: NS is a safe and effective locking solution in implantable ports if combined with a strict protocol for device insertion and maintenance.